Glutamine and Glutamate levels in autistics

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Marya
Posts: 212
Joined: Tue Feb 21, 2017 4:14 pm

Glutamine and Glutamate levels in autistics

Postby Marya » Fri Jun 16, 2017 11:03 pm

Hi everyone,
I was doing a research on Glutamine and Glutamate in autistics.
And these are my findings:
Since Glutamine increase Glutamate according to this
http://articles.mercola.com/sites/artic ... amine.aspx

How Glutamine is low in autistics and Glutamate is high as this article state?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787567/

And assuming that’s possible, how autistics benefits from Glutamine when their Glutamate is already high as Glutamine may increase it too much.
Does that mean autistics only benefits from Glutamine when their Glutamate is low?

The second part of my research is about MSM. MSM is a building block of Glycosaminoglycans, which is Glucosamine that also contribute in Glutamine synthesis. Which leads to more Glutamine then Glutamate. If I’m not mistaken both Glutamine and MSM or Glucosamine raise Glutamate level.

The last part is Glutamate receptors, N-methylD-aspartate (NMDA). How they affect the level of Glutamate in the brain?
Any researcher interested in this please?

Marya
Posts: 212
Joined: Tue Feb 21, 2017 4:14 pm

Re: Glutamine and Glutamate levels in autistics

Postby Marya » Mon Jun 19, 2017 10:41 pm

Regarding NMDA and Glutamate levels I came across this:
The effects of NMDA-receptor antagonists in animal models have shown a significant increase in glutamate release, possibly because the body is attempting to compensate for reduced signaling by releasing more of the messenger [Moghaddam and Jackson, 2003]. Excessive levels of glutamate may then overload other (non-NMDA) glutamate receptors, causing excitotoxicity and cell death. This is an interesting mechanistic proposal for how NMDA receptor dysfunction may lead to poor synapse connections and brain tissue atrophy in schizophrenia patients.

I found out that NMDA receptors dysfunction lead to excessive level of Glutamate and by addressing that dysfunction Glutamate would be under control.

Marya
Posts: 212
Joined: Tue Feb 21, 2017 4:14 pm

Re: Glutamine and Glutamate levels in autistics

Postby Marya » Mon Jun 19, 2017 11:16 pm

Regarding Glutamate and Glutamine, Here is a good thread
http://rlcure.com/glutamate2.html
The summary of it is:
Glutamine in your body is used to either build your GABA level, in turn lowering your glutamate level ... or vice versa - depending on which way they are out of balance at that time.

Glutamine is essentially a manager, determining what needs to be produced in order to keep the GABA and glutamate levels in balance.

But, there's a catch. Because you have a higher than normal amount of inflammation in your body, this can affect the transport and monitoring that are part of the Glutamate-glutamine cycle.
Dr. Mullan said:
Be careful when you read studies. You never know what the author's motive may be or who may be backing the study. Dr Amy Yasko does not recommend l-glutamine because it can turn into glutamate, especially if the GAD gene or enzyme is affected in any way.

I think Glutamine may play a role in balancing Glutamate and GABA but under some conditions that may be not available in every body so preventing it is recommended by Dr Yasko and some others doctors.
Any ideas please?

FatherOf2
Posts: 1662
Joined: Mon Mar 11, 2013 1:37 am

Re: Glutamine and Glutamate levels in autistics

Postby FatherOf2 » Mon Jul 17, 2017 11:30 pm

This is an interesting article on NMDA receptors and schizophrenia:
https://pdfs.semanticscholar.org/b396/b28a3e1ddcd7a245f2fe22ad9b0a76503713.pdf

NMDARs with NR2/NR1 subunits have been implicated in numerous physiological processes, including synaptic plasticity and development, as well as in several pathological conditions, such as neurodegenerative and psychiatric diseases... D-serine and glycine both have excitatory effects, with D-serine being up to three times more potent than glycine... Growing evidence indicates that D-serine, rather than glycine, is the dominant endogenous ligand for the D-serine/glycine site of most NMDARs... DAO is highly selective for D-serine degradation... it catalyzes the oxidative deamination of D-serine to produce anaketo acid, ammonia, and hydrogen peroxide [Fo2: my son has upregulated DAO according to his genetic test and high blood ammonia]... SNP markers within the DAO gene may confer an increased vulnerability to schizophrenia.

... Activation of astrocytic AMPA receptors stimulates D-serine release [Fo2: Piracetam is a positive allosteric modulator of AMPA receptors, which is probably why it worked so well in my son and made him talk]... Activation of metabotropic glutamate receptors (mGluR5) on astrocytes have also recently been shown to enhance D-serine production.

... Chronic exposure to NMDAR inhibitors ... lowers dopamine levels in the prefrontal cortex and affects dopamine receptor binding ..., consistent with findings in patients with schizophrenia. This suggests that aberrant dopaminergic transmission in schizophrenia may be the consequence of a defect in the regulatory glutamatergic neuronal pathway. In addition, antagonists of the NMDAR disrupt activity in the prefrontal cortex, affecting the efficiency of neuronal firing and synchronization, which may contribute to disturbances in cortical processing and cognitive function observed in schizophrenia... Kynurenic acid (KYNA) is the only known endogenous NMDAR D-serine/glycine site antagonist. It also functions as a non-competitive inhibitor of a-7 nicotinic acetylcholine receptors. Elevations in kynurenic acid have been found in the CSF and postmortem brain of schizophrenia patients.

...The NMDAR D-serine/glycine site has been proposed as a potential therapeutic target, as increasing its activation offers a safer alternative to elevations in glutamate levels that can promote neurotoxicity... An initial study assessing the clinical efficacy of D-cycloserine in conjunction with conventional medications observed a U shaped dose response curve, since as a partial agonist D-cycloserine can function as an agonist or antagonist depending on the degree of occupancy at the D-serine/glycine site... Improvements in negative and cognitive deficits were found at an optimal dose (50 mg/day) [with worsening of psychotic symptoms at higher doses]... D-Cycloserine was not found to be beneficial as adjunctive treatment in [other studies]... Disparity in findings indicates a limited therapeutic effect of D-cycloserine in the general patient population... High dose of glycine (0.8 g/kg/day) ... has demonstrated promising results... Glycine can be converted to L-serine, which can subsequently lead to the biosynthesis of D-serine. Consequently, a rise in D-serine may contribute to the therapeutic effects of large doses of glycine. Accordingly, clinical trials administering glycine treatments to schizophrenia patients have reported an elevation serum serine levels... D-serine (30 mg/kg) in combination with antipsychotic drugs was found to be therapeutically beneficial, as it considerably reduced positive, negative, and cognitive symptoms of schizophrenia... One concern with D-serine treatments has been renal toxicity, since large doses of D-serine have been found to cause reversible acute tubular necrosis in rats

... As an alternative to directly activating the NMDAR D-serine/glycine site, clinical investigations also examined sarcosine, an inhibitor of GlyT-1 that effectively raises synaptic levels of glycine. Sarcosine (2 g/day) cotreatment with conventional medications or risperidone significantly reduced positive, negative, cognitive, and general psychopathology symptoms in patients with stable chronic schizophrenia and in patients with acute exacerbation of schizophrenia.

...Though D-serine and similar compounds have demonstrated promising effects in clinical trials with medicated schizophrenia patients, there are issues regarding the administration of these compounds, as large doses are required for therapeutic effect. In contrast, DAO inhibitors cross the blood-brain-barrier readily.
Last edited by FatherOf2 on Tue Jul 18, 2017 4:28 pm, edited 2 times in total.

FatherOf2
Posts: 1662
Joined: Mon Mar 11, 2013 1:37 am

Re: Glutamine and Glutamate levels in autistics

Postby FatherOf2 » Tue Jul 18, 2017 1:20 am

So, my summary: Cognitive performance is improved by increasing D-Serine or Glycine. But high doses are needed. Sarcosine increases Glycine indirectly, by inhibiting its transport. DAO inhibitors also increase D Serine, but you have to be careful since DAO also breaks down histamine.

Some DAO inhibitors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127955/
Amoxicillin/clavulanic acid (90%)
Cimetidine - H2 antagonist and acid reducer Tagamet, sold on-line, also anti-viral (50%)
Verapamil (50%)
vit B1 (>20%)
Amitriptyline (>20%)
Metoclopramide (<20%)
Aspirin
Carnosine
Curcumin
Caffeine, nicotine, and theobromine in cocoa
D-Cycloserine
Valium

Cimetidine looks interesting. But there are case reports that it can induce psychosis (paranoia and delusions). There are absolutely no reports that this strong DAO inhibitor increases cognition. It is all very confusing! So far, it appears that Glycine or Sarcosine are the best proven choices to treat cognitive impairments in schizophrenic patients. Piracetam and Aniracetam are also interesting since they increases D-serine though activation of AMPA receptors. Also need to reduce Kynurenic acid, a byproduct of L-tryptophan conversion to niacin and serotonin. But how?

http://neurosciencenews.com/schizophrenia-kyna-psychology-6074/
...boosting glutamate on a large scale has serious side effects, including seizures and nerve cell death. Dr. Schwarcz and his colleagues propose that modifying KYNA could adjust glutamate more precisely. In recent years, he and his collaborators have in fact shown that a reduction in KYNA improves cognition in animals that have cognitive deficits similar to those seen in schizophrenia. Because this mechanism is indirect, it seems not to trigger the same side effects that directly boosting glutamate does.

https://www.ncbi.nlm.nih.gov/pubmed/7713164
Oxiracetam, aniracetam and D-cycloserine, three putative cognition enhancers, were examined in a functional assay for NMDA receptors. Rat hippocampal slices or synaptosomes were labeled with [3H]noradrenaline and exposed to NMDA or glutamate in superfusion. NMDA (100 microM) elicited a remarkable rise (about 500%) in the release of [3H]noradrenaline from slices. The effect of NMDA was antagonized by the glutamate receptor blocker, kynurenic acid. The antagonism by 100 microM kynurenate was reduced by submicromolar concentrations of oxiracetam and totally reversed by 1 microM of the drug. The concentration-antagonism curve for kynurenic acid was shifted to the right in the presence of 0.2 or 1 microM oxiracetam. [url]Aniracetam and D-cycloserine, as well as glycine and D-serine, behaved similarly to oxiracetam: all compounds, tested at 1 microM, reversed the antagonism by 100 microM kynurenate of the NMDA-evoked [3H]noradrenaline release[/url]. In superfused hippocampal synaptosomes, 100 microM NMDA or glutamic acid elicited the release of [3H]noradrenaline; the evoked release was enhanced by glycine, but not by oxiracetam. In this preparation 1 microM glycine or 1 microM oxiracetam prevented the antagonism by kynurenate of the NMDA- or the glutamate-evoked [3H]noradrenaline release. As kynurenic acid is an endogenous glutamate receptor antagonist whose brain levels are known to increase in conditions associated to cognitive deficits, it is proposed that the putative cognition enhancers tested may act in vivo by relieving the antagonism produced by excessive endogenous kynurenate.

By the way, tryptophan increases KYNA and reduces cognition: https://www.ncbi.nlm.nih.gov/pubmed/12655316


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